E3: A 'Glimmer of Hope' and Renewed Concerns Over E-Cigarettes

Patrice Wendling

April 01, 2020

The first large North American study to directly test the question of whether e-cigarettes help tobacco smokers quit suggests an early benefit but with little long-term data to allay growing safety concerns.

Progress among the participants (mean age, 52 years; 53% male) was checked during three phone calls and two clinic visits that included carbon monoxide testing.

At the 12-week visit, 22% of participants assigned nicotine e-cigarettes quit smoking traditional cigarettes, compared with 9% given counseling alone. With non-nicotine e-cigarettes, the proportion fell in between at 17%.

"We asked subjects at 12 weeks whether they thought they got an e-cigarette with or without nicotine and only 50% of them were right in both arms; they couldn't tell," lead author Mark J. Eisenberg, MD, McGill University, Montreal, told theheart.org | Medscape Cardiology. "It's interesting, just having that e-cigarette helped a lot of people give up cigarettes, at least for 12 weeks."

Even with the use of pharmacologic or behavioral therapy, well over two-thirds of those attempting to quit return to smoking within 1 year, he noted during his late-breaking presentation at the virtual American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology.

Indeed, 91% of the participants had previously tried to quit, 80% had used aids, such as smoking-cessation medications or behavioral therapy, and 36% had already tried e-cigarettes.

The researchers also measured continuous abstinence, in which participants were counted as having failed if they reported smoking even one puff of cigarette at week 1. By this more rigorous measure, the nicotine and non-nicotine e-cigarette groups did slightly better than the counseling-alone group at each time point, with rates reaching 5%, 3%, and 1%, respectively, at 12 weeks, Eisenberg said.

The average number of cigarettes smoked per day fell from 21 at baseline to 14 at 12 weeks in the counseling-alone group, 10 in the non-nicotine e-cigarette group, and eight in the nicotine e-cigarette group. As expected, dropout was more common in the counseling-only group because many people enrolled hoping to get e-cigarettes, he noted.

Given that relapse is known to be very common after quitting, panelist Nancy Rigotti, MD, Massachusetts General Hospital, Boston, observed that the norm for smoking-cessation trials is to present at least 6 months and ideally 12 months of follow-up to ensure the intervention leads to permanent cessation.

"Twelve weeks is really the 'end of treatment' point," she said.

E3 was planned to run for 52 weeks, but a prolonged e-cigarette manufacturing delay forced enrolment to be halted at 77% of the planned enrollment and the timing of the primary end point was changed to 12 weeks, given the reduction in power, Eisenberg explained. Longer-term 6- and 12-month data will be assessed to "determine if the benefits we saw persist over time."

Safety Data

At 12 weeks, there were few serious adverse events, which were adjudicated and determined to be unrelated to the interventions, Eisenberg said. They were one COPD exacerbation in the nicotine e-cigarette group; appendicitis, neoplastic cecal lesion, myocardial infarction, chest pain, and epistaxis (one each) in the non-nicotine e-cigarette group; and one critical limb ischemia and one urinary tract infection in the counseling group.

Still, clinicians are struggling over whether to recommend e-cigarettes for smoking cessation. In addition to reports of e-cigarette or vaping-associated lung injury (EVALI), data are emerging suggesting increased risks for pulmonary disease and cardiovascular events.

The devices used in the study were closed units, so it was not possible to adulterate the liquid with vitamin E acetate or other additives, Eisenberg said in an interview. E-cigarette liquid can expose users to ultrafine particles, aldehydes, but levels are lower than in traditional cigarettes, he noted.

"I'm pretty sure how the e-cigarette makers will tout this study and that concerns me," Martha Gulati, MD, chief of cardiology at the University of Arizona College of Medicine, Phoenix, told theheart.org | Medscape Cardiology. "They will say they help people quit and they're going to tell us that's evidence enough.

"This is a small study, it's only 12 weeks, it doesn't answer the question that it [an e-cigarette] is effective in helping people quit, nor does it address anything about safety," she added. "The long-term ability of this to help people quit is one part, and the safety is, of course, a second and equal part. Because if something makes you quit but its gonna kill you in a different way, we need to know that too."

Gulati said she strongly believes the US Food and Drug Administration (FDA) should regulate e-cigarettes. E-cigarettes are recommended as a smoking-cessation tool in the United Kingdom, but the ACC and American Heart Association have yet to endorse their use because of the lack of data, she noted.

Speaking to theheart.org | Medscape Cardiology, preventive cardiologist Pamela Morris, MD, Medical University of South Carolina, Charleston, said the study offers a "glimmer of hope," but that she shares Gulati's concerns about how the results will be interpreted.

"If I knew I had a highly regulated product that had controlled manufacturing and a good definition of nicotine content and the other substances that are within the suspension of the nicotine, I could be someone who would be optimistic that it provides a potential tool, ultimately," she said. "But I think we have to be careful not to let this be the wild, wild West, and that is what I'm afraid of — that headlines could overhype these things."

Morris also called for more regulation, beginning with a clear definition of what constitutes an e-cigarette.

"We're going to have to define what is an e-cigarette because it's not any product out there and any product out there used any way you please," she said. "Then we're also going to have to weigh it in the balance of the risk to youth and the risk to nonsmokers who may be tempted to take these products.

"There's some reassuring information that there's safety and benefit with a controlled product in a controlled setting along with counseling and careful supervision," she said. "But we need the long-term data and it all needs to be balanced against all of the other concerns."

As part of the panel discussion, Rigotti also pointed out that e-cigarettes are a "moving target" and that their design is rapidly evolving. The best-selling products are now the pod mods sold by Juul Labs and others, which deliver a higher dose of nicotine and do so more rapidly than the second-generation device that was tested.

As such, might the results be different if a Juul e-cigarette were tested, she asked.

"My father was a doctor; he told me he liked to see 10 different studies in 10 different patient populations with 10 different products before he would consider accepting the results, so I think that's true here," Eisenberg replied.

The researchers actually contacted Juul when this began, "but they didn't even want to talk to us to do a trial," he said.

When interviewed, Eisenberg said he'd like to see a smoking-cessation trial comparing varenicline (Chantix) plus e-cigarettes, given the data from the EAGLES trial. And in the meantime?

"Personally, I think they should only be used by people who are trying to quit smoking," he said. "I don't think they should be used by youth; I don't think they should be used by people who have never smoked. In fact, I could conceive of a situation where e-cigarettes were only prescribed by physicians for smoking cessation, in the same way we prescribe varenicline, bupropion, or a nicotine patch."

As part of an ongoing lawsuit, e-cigarette manufacturers have until May 12 to apply to the FDA and demonstrate a public-health benefit in order to keep their products on the market. Because of the COVID-19 pandemic, however, the FDA has asked the court to extend that deadline until September 9, according to a statement issued today by several professional medical groups that are plaintiffs in the lawsuit. Last week, the FDA told Bloomberg News that vaping may leave users with underlying health conditions at higher risk for serious complications from COVID-19.

E3 was sponsored by McGillUniversity. Coauthor Wilderman received financial compensation from Pfizer for his involvement in a smoking-cessation study using varenicline. The other authors, Gulati, and Harris reported having no relevant conflicts of interest.

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